U.S. patent number 4,364,958 [Application Number 06/169,439] was granted by the patent office on 1982-12-21 for 1-substituted-3-cycloalkyl-sulfonyl-pyrrolidine-2,5-dione derivatives and fungicidal compositions thereof.
This patent grant is currently assigned to Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Rt.. Invention is credited to Gabor Kulcsar, Jeno Seres, Erika Varkonyi nee Schlavicsko, Sandor Virag.
United States Patent |
4,364,958 |
Seres , et al. |
December 21, 1982 |
1-Substituted-3-cycloalkyl-sulfonyl-pyrrolidine-2,5-dione
derivatives and fungicidal compositions thereof
Abstract
A fungicidal compound of the formula: ##STR1## wherein A is
C.sub.5-10 cycloalkyl, R is hydrogen, C.sub.1-6 alkyl, phenyl
optionally substituted by one or more groups selected from
C.sub.1-4 alkyl, nitro, hydroxy, carboxy, sulfo, sulfonylamino,
halogen, C.sub.1-4 alkoxy, C.sub.1-4 acyloxy, C.sub.2-5
alkoxycarbonyl, C.sub.1-4 acyl, and N-(C.sub.2-5
alkoxycarbonyl)-sulfonylamino, or phenyl-(C.sub.1-4 alkyl) or a
salt thereof.
Inventors: |
Seres; Jeno (Budapest,
HU), Varkonyi nee Schlavicsko; Erika (Budapest,
HU), Virag; Sandor (Budapest, HU), Kulcsar;
Gabor (Budapest, HU) |
Assignee: |
Chinoin Gyogyszer es Vegyeszeti
Termekek Gyara Rt. (Budapest, HU)
|
Family
ID: |
10994755 |
Appl.
No.: |
06/169,439 |
Filed: |
July 16, 1980 |
Foreign Application Priority Data
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Jul 17, 1979 [HU] |
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CI 1951 |
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Current U.S.
Class: |
514/425;
548/544 |
Current CPC
Class: |
C07D
207/416 (20130101); C07D 207/46 (20130101); A61P
31/04 (20180101); A61P 31/10 (20180101) |
Current International
Class: |
C07D
207/00 (20060101); C07D 207/46 (20060101); C07D
207/416 (20060101); C07D 207/416 (); A01N
043/36 () |
Field of
Search: |
;260/326.41,326.5SF |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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752109 |
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Dec 1970 |
|
BE |
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2143601 |
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Mar 1972 |
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DE |
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70/01621 |
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Mar 1970 |
|
ZA |
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Other References
Kato, Bull. Chem. Soc., Japan, 48, 3675-3677, (1975). .
Hackh's Chemical Dictionary..
|
Primary Examiner: Berch; Mark L.
Attorney, Agent or Firm: Ross; Karl F.
Claims
We claim:
1. A compound of the formula (I) ##STR9## wherein A is C.sub.5 to
C.sub.10 cycloalkyl; and
R is hydrogen, C.sub.1 to C.sub.6 alkyl, phenyl optionally
substituted by either one or two substituents wherein the
substituents are selected from the group consisting of C.sub.1 to
C.sub.4 alkyl, nitro, hydroxy, carboxy, sulfo, halogen, C.sub.1 to
C.sub.4 alkoxy, acetoxy, C.sub.2 to C.sub.5 alkoxycarbonyl, and
acetyl, or phenyl-(C.sub.1 to C.sub.4 alkyl).
2. 1-Phenyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione as defined
in claim 1.
3. 3-Cyclohexyl-sulfonyl-pyrrolidine-2,5-dione as defined in claim
1.
4. 1-(p-Tolyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione as
defined in claim 1.
5. 1-(3-A
cetoxy-4-methoxycarbonyl-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dion
e as defined in claim 1.
6. 1-(3-Acetoxy-4-carbox
y-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione as defined in
claim 1.
7. 1-Ethyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione.
8. 1-n-Hexyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione as defined
in claim 1.
9. 1-(2-Chlorphenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione as
defined in claim 1.
10. 1-(3-Nitrophenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
as defined in claim 1.
11. 1-(4-Acetylphenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
as defined in claim 1.
12. A fungicidal pharmaceutical composition comprising a
fungicidally effective amount of at least one
1-substituted-3-cycloalkyl-sulfonyl-pyrrolidine-2,5-dione of the
formula I as defined in claim 1, together with a conventionally
used fungicidally acceptable filling agent.
13. 1-(4-Methoxyphenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
as defined in claim 1.
14. A fungicidal composition comprising about 1-80% of a compound
of the formula I as defined in claim 1 fungicidally acceptable salt
thereof, and 0-20% colloidal silicic acid, 0-10% surfactants, 0-20%
mineral filling agents, 0-10% protective colloids, 0-80% starch,
0-50% glycerol, 0-15% water or 0-99% inert, atoxic, organic solvent
and 0-60% spray propellant.
15. 1-Benzyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione as defined
in claim 1.
16. 1-Phenyl-3-cyclooctyl-sulfonyl-pyrrolidine-2,5-dione as defined
in claim 1.
17. 1-Phenyl-3-cyclopentyl-sulfonyl-pyrrolidine-2,5-dione as
defined in claim 1.
18. 1-(p-Tolyl)-3-cyclopentyl-sulfonyl-pyrrolidine-2,5-dione as
defined in claim 1.
19. 1-(p-Sulfo-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
as defined in claim 1.
20.
1-(4-Methyl-2-sulfo-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
as defined in claim 1.
21.
1-(3,4-Dihydroxy-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
as defined in claim 1.
22. 1-(4-Methyl-3-ca
rboxy-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione as
defined in claim 1.
23. 1-(4-
Methyl-2-hydroxymethyl-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
as defined in claim 1.
Description
The invention relates to new
1-substituted-3-cycloalkyl-sulfonyl-pyrrolidine-2,5-dione
derivatives of the formula I as well as to fungicidal compositions
containing the new compounds as active ingredients and a process
for the preparation of the compositions.
In the formula I ##STR2## A is C.sub.5-10 cycloalkyl, R is
hydrogen, C.sub.1-6 alkyl, phenyl optionally substituted by one or
more of C.sub.1-4 alkyl, nitro, hydroxy, carboxy, sulfo, halogen,
C.sub.1-4 alkoxy, C.sub.1-4 acyloxy, C.sub.2-5 alkoxycarbonyl, or
C.sub.1-4 acyl, or phenyl-(C.sub.1-4 alkyl).
The new 1-substituted 3-cycloalkyl-sulfonyl-pyrrolidine-2,5-dione
derivatives possess strong fungicidal activity and thus are
suitable for combatting human, veterinary and phytopathological
fungi.
N-(3,5-dihalophenyl)-3(,4)-(di)-substituted-pyrrolidine-2,5-dione
derivatives have been reported to possess antimicrobial activity
(South African Patent Specification No. 701 624).
Compounds of similar structure, i.e.
N-(2,6-disubstituted-phenyl)-3-substituted-pyrrolidine-2,5-dione
derivatives are disclosed in West-German Patent Publication No. 2
143 601. The compounds display antimicrobial activity.
The coupling reaction of N-aryl-maleinimides and phenyl sulfinic
acid is disclosed in Bull. of the Chem. Soc. of Japan 48 (12),
3675-3677 (1975). No utility of the compounds is disclosed in the
article.
As microbes become resistant to the active ingredients used,
therapy continuously requires new antimicrobial ingredients.
It has been found that the new
1-substituted-3-cycloalkyl-sulfonyl-pyrrolidine-2,5-dione
derivatives of the formula I possess antimicrobial, mainly
fungicidal activity, even against microorganisms which have become
resistant to the conventionally used fungicidally active
ingredients.
According to the invention the new
1-substituted-3-cycloalkyl-sulfonyl-pyrrolidine-2,5-dione
derivatives are prepared by
(a.sub.1) coupling a cycloalkyl-thiol of the formula III
with a 1-substituted-pyrroline-2,5-dione of the formula II ##STR3##
and oxidizing the obtained
1-substituted-3-cycloalkylthio-pyrrolidine-2,5-dione derivative of
the formula IV ##STR4## or
(a.sub.2) oxidizing a
1-substituted-3-cycloalkylthio-pyrrolidine-2,5-dione of the formula
IV ##STR5##
(b) coupling a cycloalkyl-sulfinic acid of the formula V
with a 1-substituted-pyrroline-2,5-dione of the formula II ##STR6##
or
(c) reacting a 1-substituted-3-halo-pyrrolidine-2,5-dione of the
formula VI ##STR7## with an alkali metal sulfonate of the formula
VI
or
(d) treating a cycloalkyl-sulfonyl-succinic acid semiamide of the
formula VIII ##STR8## where X is halogen, with an alkali metal
sulfinate of the formula VII --NH--R-- wherein R is as given
above--with a water binding agent.
The reaction of 1-substituted-pyrroline-2,5-dione of the formula II
and cycloalkyl-thiol of the formula III according to process
variant (a.sub.1) may optionally be carried out in the presence of
an inert organic solvent and/or a basic catalyst. As suitable
organic solvents aromatic hydrocarbons, such as benzene, ethers,
such as dioxane, alcohols, such as ethanol may be employed. As
basic catalysts organic or inorganic basis are preferred. As
examples for the basic catalysts triethylamine or triethylene
diamine may be mentioned. Reactants of the formula II and III are
preferably used in equimolar amounts, but in some cases one of the
reactants may be employed in excess.
1-substituted-3-cycloalkylthio-pyrrolidine-2,5-dione derivatives of
the formula IV obtained in the course of the above reaction may be
recovered by evaporation of the reaction mixture. The evaporation
may be performed at atmospheric pressure or at reduced
pressure.
1-Substituted-3-cycloalkylthio-pyrrolidine-2,5-dione derivatives of
the formula IV may be oxidized by dissolving or suspending the
compound in an inert solvent, such as water, lower ketones, such as
acetone, lower alkane carboxylic acids, lower alkane carboxylic
acid anhydrides, or a suitable mixture of the mentioned solvents,
such as an 1:1 mixture of acetic acid and acetic anhydride and
oxidizing the obtained product preferably at 0.degree. to
50.degree. C. with an oxidizing agent, such as hydrogen peroxide or
potassium permanganate. The oxidizing agent is preferably used in
excess.
Compounds of the formulae II and V according to process variant (b)
are reacted preferably by dissolving or suspending the compound of
the formula II in a mixture of water and a lower alkanol and
cycloalkyl sulfinic acid of the formula V is added to this solution
or suspension under stirring preferably at 0.degree. to 25.degree.
C. Under the above-mentioned conditions the reaction is completed
within a few hours and--the compound of the formula I is
precipitating from the reaction mixture.
1-substituted-3-halo-pyrrolidine-2,5-dione of the formula VI and
alkali metal-sulfinate of the formula VII are preferably reacted in
an inert polar aprotic solvent, such as dimethylformamide. When
using equimolar reactants, the reaction is complete within 30-120
minutes at a temperature ranging from 15.degree. to 35.degree.
C.
Dehydration of cycloalkyl-sulfonyl-succinic acid semiamides of the
formula VIII is preferably conducted in an excess of the water
binding agent, such as phosphorus pentoxide, phosphorus
trichloride, acetyl chloride, acetic anhydride. Dehydration is
preferably performed in an inert organic solvent. It is
particularly preferred to use the same substance as water binding
agent and as solvent. Acetic anhydride may be used for example as a
solvent and as a water binding agent as well. The reaction may be
accelerated by heating. The reaction temperature is generally
within a range from 20.degree. C. to 140.degree. C., preferably
from 90.degree. to 95.degree. C.
The formed compounds of the formula I are precipitated from the
mixture or are isolated by filtration, centrifuging or remain in
the solution. In the latter case the reaction mixture is usually
processed by isolating the by-products--if any--by filtration
followed by pouring the reaction mixture on ice or water and
isolating the thus precipitated product. According to another
method the volatile components and the solvent are distilled off
from the mixture optionally at reduced pressure and the obtained
residue is purified by recrystallization. Recovery and purification
of the end products may be conducted by any other conventionally
used technique.
The lower alkyl, alkoxy, alkanoyl and alkane carboxylic acid and
alkane carboxylic acid anhydride groups of the invention contain
alkyl groups having 1 to 4 carbon atoms.
Compounds of the formulae II, V, VII, VI and VIII used as starting
materials in the process according to the invention are known or
may be obtained by methods known per se. 1-Substituted
3-pyrroline-2,5-diones of the formula II may be obtained by
reacting maleic acid anhydride with a corresponding amine followed
by treating the obtained 4-substituted-amino-4-oxo-butenoic acid
with a water binding agent. (Wiss. Z. Univ. Halle XXV' 76M, 4, 5
(1976) and J. Org. Chem., 26, 2037 (1961).
Sulfinic acids of the formula V and salts thereof of the formula
VII may be prepared by methods disclosed in the state of art (J.
Amer. Chem. Soc., 61, 3089 (1939), Org. Synth., Coll. Vol. I 492
(1943), J. Org. Chem., 17, 1529 (1952) and the cited
references.
1-Substituted 3-halo-pyrrolidine-2,5-diones of the formula VI may
be prepared by similar methods as disclosed in Obscs. Him., 26, 208
(1956), J. Org. Chem. 28, 1713 (1963) and South African Pat. Spec.
No. 70.01624.
Compounds of the formula VIII may be prepared for example by
coupling 4-substituted amino-4-oxo-butenoic acids with
cycloalkyl-thiols-prepared as given above--according to process
variant (a.sub.1) and oxidizing the obtained product as disclosed
in process variant (a.sub.2).
Some of the starting materials are commercially available. The
fungicidal activity of the compounds of the formula I of the
invention was investigated as follows:
Sabouraud medium was inoculated with 10.sup.5 /ml. germ number and
the propagation of the fungi was examined after 24, 48, 72, 144 and
288 hours incubation time and the minimal inhibitory concentrations
were determined.
The obtained results are summarized in Tables I and II.
The following test organisms were used.
______________________________________ Saccharomyces cerevisiae
OKI.1282 "1" Candida albicans CBS.562 "2" Candida tropicalis
CBS.433 "3" Aspergillus niger CBS.12648 "4" Aspergillus niger
CCM.F-330 "20" Aspergillus fumigatus CBS.11326 "5" Aspergillus
flavus CBS.24765 "6" Penicillium digitatum CBS.31948 "7"
Penicillium digitatum CCM.F-382 "8" Penicillium chrysogenium
CBS.19646 "9" Penicillium chrysogenium CCM.F-362 "10" Microsporum
gypseum ver. vinosum CBS.10064 "11" Sporotrichum schenkii CBS.34035
"12" Trichophyton rubrum CBS.30338 "13" Trichophyton mentagrophytes
CBS.50148 "14" Epidermophyton floccosum OKI/IV. "15" Fusarium
graminocorum DSM.11802 "16" Fusarium oxysporum DSM.10975 "17"
Fusarium monoliforme DSM.11778 "18" Fusarium culmorum DSM.11425
"19" Candida krusei 79/K47 "21" Cryptococcus neoform. 78/K16 "22"
______________________________________
In the Tables the names of the microorganisms are replaced by their
number as given above.
Abbreviations after the name of the microorganisms:
CBS.: Centralbureau voor Schimmelcultures, Baarn, Netherlands
CCM.: Czechoslovak Collection of Microorganism, J. E. Purkyne,
University Brno, C6SR.
DSM.: Deutsche Sammlung fur Mikroorganismen, Institute of Mycology,
Berlin-Dahlem, Federal Republic of Germany,
OKI.: Orszagos Kozegeszsegtani Intezet, Budapest.
LD.sub.50 of N-pheny-3-cyclohexyl-sulfonyl-pyrrolidine-2,3-dione
when applied intraperitoneally
female mice: 382 mg./kg.
male mice: 461 mg./kg.
No toxic properties of the compounds were observed when
administered perorally.
TABLE I
__________________________________________________________________________
1-(p-tolyl)-3-cyclo- 1-phenyl-3-cyclohexyl-sulfonyl-
hexyl-sulfonyl-pyrro- Test- pyrrolidine-2,5-dione lidine-2,5-dione
micro- minimal inhibitory concentrations .mu.g/ml organism 24 48 72
144 288 hours 24 48 72 144 288 hours
__________________________________________________________________________
"1" 50 50 -- -- -- 25 25 -- -- -- "2" 75 100 -- -- -- 25 50 -- --
-- "3" 150 150 -- -- -- 100 150 -- -- -- "4" -- -- 75 150 150 -- --
25 75 75 "5" -- -- 50 150 150 -- -- 50 150 150 "6" -- -- 100 200
250 -- -- 150 250 -- "7" -- -- 10 25 25 -- -- 10 10 10 "8" -- -- 25
50 75 -- -- 25 25 75 "9" -- -- 50 75 75 -- -- 50 75 75 "10" -- --
75 200 200 -- -- 75 150 150 "11" -- -- 10 10 10 -- -- 10 25 25 "12"
-- -- 10 10 50 -- -- 5 10 25 "13" -- -- 2.5 10 10 -- -- 2.5 5 5
"14" -- -- 5 10 10 -- -- 2.5 2.5 5 "15" -- -- 2.5 5 5 -- -- 5 5 5
"16" -- -- 50 100 100 -- -- 50 50 50 "17" -- -- 50 75 75 -- -- 150
200 200 "18" -- -- 100 150 150 -- -- 100 150 150 "19" -- -- 50 50
100 -- -- 75 150 150 "20" -- -- 150 200 250 -- -- 100 150 250 "1"
75 75 -- -- -- 10 25 -- -- -- "2" 50 50 -- -- -- 10 25 -- -- -- "3"
75 75 -- -- -- -- -- -- -- -- "4" -- -- 75 150 150 -- -- 25 50 75
"5" -- -- 50 150 200 -- -- -- -- -- "6" -- -- 75 150 200 -- -- --
-- -- "7" -- -- 10 25 50 -- -- 10 10 10 "8" -- -- 10 50 50 -- -- --
-- -- "9" -- -- 50 75 150 -- -- -- -- -- "10" -- -- 75 150 200 --
-- -- -- -- "11" -- -- 10 25 25 -- -- -- -- -- "12" -- -- 50 75 100
-- -- 5 25 25 "13" -- -- 2.5 10 10 -- -- 1 2.5 2.5 "14" -- -- 2.5
10 25 -- -- 2.5 2.5 5 "15" -- -- 1 2.5 10 -- -- 2.5 5 5 "17" -- --
50 75 75 -- -- -- -- -- "18" -- -- 75 150 200 -- -- -- -- -- "20"
-- -- 75 150 150 -- -- -- -- -- "21" 10 10 -- -- -- -- -- -- -- --
"22" 25 25 -- -- -- -- -- -- -- --
__________________________________________________________________________
TABLE II
__________________________________________________________________________
1-(2-acetoxy-4-methoxy- 1-(p-nitrophenyl)-3-cyclo-
3-cyclohexylsulfonyl- carbonyl-phenyl)-3-cyclohexyl -
hexylsulfonyl-pyrrolidine- pyrrolidine-2,5-
sulfonyl-pyrrolidine-2,5- Test- 2,5-dione dione dione micro-
minimal inhibitory concentrations .mu.g/ml organism 24 48 72 144
288 hours 24 48 72 144 288 hours 24 48 72 144 288 hours
__________________________________________________________________________
"1" 25 50 -- -- -- -- -- -- -- -- -- -- -- -- -- "2" 75 150 -- --
-- -- -- -- -- -- -- -- -- -- -- "4" -- -- 75 150 150 -- -- -- --
-- -- -- 200 200 200 "7" -- -- 100 150 150 -- -- 50 50 50 -- -- 50
50 100 "12" -- -- 25 25 25 -- -- 150 150 150 -- -- 50 100 150 "13"
-- -- 75 75 150 -- -- 50 75 75 -- -- 25 25 50 "14" -- -- 75 100 100
-- -- 50 50 75 -- -- 2.5 2.5 2.5 "15" -- -- 100 150 150 -- -- 25 25
25 -- -- 10 10 10
__________________________________________________________________________
1-(o-tolyl)-3-cyclohexyl- 1-m(tolyl)-3-cyclohexyl-
1-(p-methoxyphenyl)-3-cyclo- 9 sulfonyl-pyrrolidine-
sulfonyl-pyrrolidine- hexylsulfonyl-pyrrolidine- Test 2,5-dione
2,5-dione 2,5-dione micro- minimal inhibitory concentrations
.mu.g/ml organism 24 48 72 144 288 hours 24 48 72 144 288 hours 24
48 72 144 288 hours
__________________________________________________________________________
"1" 25 25 -- -- -- 25 25 -- -- -- 25 50 -- -- -- "2" 75 100 -- --
-- 50 100 -- -- -- 50 150 -- -- -- "4" -- -- 100 150 150 -- -- 75
100 150 -- -- 75 100 150 "7" -- -- 10 50 50 -- -- 10 25 25 -- --
100 100 150 "12" -- -- 10 25 50 -- -- 10 25 50 -- -- 5 10 10 "13"
-- -- 10 25 50 -- -- 5 10 25 -- -- 10 10 10 "14" -- -- 10 25 25 --
-- 5 25 50 -- -- 2.5 75 100 "15" -- -- 5 10 10 -- -- 5 10 25 -- --
5 25 75
__________________________________________________________________________
1-(p-acetylphenyl)-3-cyclo- 1-(o-chlorphenyl)-3-cyclo-
1-(m-chlorphenyl)-3-cyclo- hexylsulfonyl-pyrrolidine-
hexylsulfonyl-pyrrolidine- hexylsulfonyl-pyrrolidine- Test-
2,5-dione 2,5-dione 2,5-dione micro- minimal inhibitory
concentrations .mu.g/ml organism 24 48 72 144 288 hours 24 48 72
144 288 hours 24 48 72 144 288 hours
__________________________________________________________________________
"1" 25 50 -- -- -- 25 75 -- -- -- 10 25 -- -- -- "2" 50 75 -- -- --
50 50 -- -- -- 25 75 -- -- -- "4" -- -- 75 150 150 -- -- 50 150 150
-- -- 50 100 100 "7" -- -- 75 100 150 -- -- 25 50 50 -- -- 10 50 50
"12" -- -- 5 25 25 -- -- 10 50 50 -- -- 10 25 25 "13" -- -- 10 25
50 -- -- 2.5 10 10 -- -- 2.5 2.5 2.5 "14" -- -- 10 25 25 -- -- 2.5
5 5 -- -- 2.5 2.5 2.5 "15" -- -- 25 50 75 -- -- 2.5 5 10 -- -- 2.5
5 10
__________________________________________________________________________
1-(o-nitrophenyl)-3-cyclo- hexyl-sulfonyl-
1-(m-nitrophenyl)-3-cyclohexy l- Test- pyrrolidine-2,5-dione
sulfonyl-pyrrolidine-2,5-dion e micro- minimal inhibitory
concentrations .mu.g/ml. organism 24 48 72 144 288 hours 24 48 72
144 288 hours
__________________________________________________________________________
"1" 100 200 -- -- -- 75 75 -- -- -- "2" 75 150 -- -- -- 50 100 --
-- -- "4" -- -- 150 200 200 -- -- 75 150 150 "7" -- -- 25 50 50 --
-- 25 50 50 "12" -- -- 10 50 50 -- -- 25 75 75 "13" -- -- 50 50 75
-- -- 5 5 5 "14" -- -- 75 150 150 -- -- 2.5 5 25 "15" -- -- 75 100
150 -- -- 5 10 10
__________________________________________________________________________
Minimal inhibitory concentrations in .mu.g/ml medium of
1-(p-tolyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione are given
after 24 and 48 hours observation period for the most important
pathogenic proliferating fungi:
______________________________________ minimal inhibitory
concentration proliferating fungi 24 hours 48 hours
______________________________________ Candida benhamii 25 75
Candida guilliermondii 5 10 Candida humicola 5 25 Candida krusei
(79/K47) 2.5 10 Candida lipolytic 5 10 Candida parapsilosis 10 50
Candida pseudotropic 2.5 10 Candida valida 5 10 Candida vini 1 5
Cryptococcus neoform (78/K16) 1 10
______________________________________
The given minimal inhibitory concentrations completely inhibited
the growth of the microorganisms. As a medium Saboroud medium was
employed.
1-(p-Tolyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione and
1-phenyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione were active
against the following phytopathogenic fungi too: Botrytis cinerea,
Ascochyta pisi, Cercospora beticola, Taphrina deformans,
Phytophtora infestans, Sclerotinia sclerotiorum, Verticillium
albo-atrum, Verticillium dahlise and Venturia.
The 1-substituted-3-cycloalkyl-sulfonylpyrrolidine-2,5-dione
derivatives of the invention may be used due to their strong
fungicidal activity as active ingredients of fungicidal
compositions. One or more compounds of the formula I may be
formulated by using the conventional filling agents, diluents,
stabilizing and/or flavoring agents and/or formulating excipients.
The compositions may be in solid, liquid or semi-liquid form. As
solid compositions tablets, capsules, troches, pellets, pills and
powders may be mentioned. The tablets may be scored. The coating of
the dragees and the capsules may optionally be indicated by a color
code according to the active ingredient content. As liquid
preparations lotions, sprayable formulations, dressing agents,
liquid medicines, injectable solutions, aerosols etc. may be used.
As semi-liquid compositions ointments, pastes or creams may be
used.
Fungicidal compositions according to the invention contain as main
active ingredient a compound of the formula I or a salt thereof in
an amount of 1-80%--wherein R and A are as given above--and 0-20%
colloidal silicic acid, 0-10% surfactant, 0-20% mineral filling
agent, 0-5% mucous substance, 0-10% protective colloid, 0-80%
starch, 0-50% glycerol, 0-15% water, 0-99% indifferent, atoxic
organic solvent and 0-60% spray propellant.
The following Examples show details of the preparation of the
compounds of the formula I and of the fungicidal compositions
containing a compound of the formula I as active ingredient. The
Examples serve for illustration and not for limitation.
EXAMPLE 1
3-Cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
In a mixture of 15 ml. of glacial acetic acid and 15 ml. of acetic
anhydride 3.19 g. (0.015 mole) of
3-cyclohexylthio-pyrrolidine-2,5-dione are suspended. 7.2 ml.
(0.075 mole) of a 30% hydrogen peroxide solution is added dropwise
to the suspension under stirring and cooling with icy water and the
system is then completely dissolved at room temperature. The
solution is then cooled down again to a temperature ranging from
0.degree. C. to 5.degree. C. and stirred for 5 hours at this
temperature. The mixture is then allowed to stand overnight and
poured to crushed ice. The precipitated product is filtered off and
washed with water to remove acid. 2.6 g. (71%) of the named product
are obtained. M.p.: 159.degree.-160.degree. C. After
recrystallization from water m.p.: 160.degree.-162.degree. C.
Minimal inhibitory concentration: inhibiting the growth of
Trychophyton metagrophytes: 50 .mu.g./ml. of Epidermophyton
floccosum: 25 .mu.g./ml.
EXAMPLE 2
1-Phenyl- 3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
In a mixture of 10 ml. of glacial acetic acid and 10 ml. of acetic
acid anhydride 2.89 g. (0.01 mole) of
1-phenyl-3-cyclohexylthio-pyrrolidine-2,5-dione are suspended. A
30% solution of 4.8 ml. (0.5 mole) hydrogen peroxide is added
dropwise to the suspension under cooling with icy water and
stirring. The reaction mixture is maintained at room temperature by
external cooling until a complete solution is obtained whereafter
the mixture is stirred for 5 hours under cooling with ice and
water. The mixture is allowed to stand for one day and the
precipitated product is filtered and washed with water to remove
acid. 3.18 g. of the named compound are obtained. Yield: 99%. M.p.:
149.degree.-151.degree. C.
EXAMPLE 3
1-Phenyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
A solution of 0.296 g. (0.002 mole) of cyclohexyl sulfinic acid in
100 ml. of water is added to a solution of 0.346 g. (0.002 mole)
1-phenyl-pyrroline-2,5-dione in 100 ml. of ethanol at 15.degree. C.
under stirring. When the addition is completed the reaction is
stirred for further 10 hours at 15.degree. C. The precipitated
product is filtered and washed with water. 0.475 g. (74%) of the
named product is obtained, m.p.: 149.degree.-151.degree. C.
EXAMPLE 4
1-Phenyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
To a solution of 2.54 g. (0.01 mole) of
1-phenyl-3-bromo-pyrrolidine-2,5-dione in 50 ml. of
dimethylformamide 1.70 g. (0.01 mole) of sodium
cyclohexyl-sulfinate are added at 30.degree. C. under stirring. The
stirring is then continued for 2 hours and the reaction mixture is
then diluted with water to a tenfold volume and the precipitated
named compound is filtered. After washing and drying 2.63 g. (82%)
of the named compound are obtained, m.p.: 148.degree.-151.degree.
C.
EXAMPLE 5
1-Phenyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
3.39 g. (0.01 mole) of
2-cyclohexyl-sulfonyl-4-phenylamino-4-oxo-butanoic acid are
dissolved in 20 ml. of acetic acid anhydride and 0.82 g. (0.01
mole) anhydrous sodium acetate and the solution is heated for 1
hour at 100.degree. C. The reaction mixture is then poured on
crushed ice and the precipitated compound named filtered off and
washed with water in order to remove acid. 2.76 g. (86%) of the
named compound are obtained. M.p.: 149.degree.-151.degree. C. After
recrystallization from methanol m.p.: 150.degree.-152.degree. C.
Minimal inhibitory concentration inhibiting the growth of
Trychophyton mentagrophytes: 2.5 .mu.g/ml. and of Epidermophyton
floccosum: 1.0 .mu.g./ml.
EXAMPLE 6
1-(p-Tolyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
4.54 g. (0.015 mole)
1-(p-tolyl)-3-cyclohexylthiopyrrolidine-2,5-dione are suspended in
a mixture of 15 ml. of glacial acetic acid and 15 ml. of acetic
acid anhydride and under cooling with icy water and under stirring
7.2 ml. (0.075 mole) of 30% hydrogen peroxide solution is added
dropwise. The reaction mixture is kept at room temperature until a
complete solution is obtained. The mixture is then cooled to
0.degree. to 5.degree. C. and the mixture is stirred at this
temperature for 5 hours. The reaction mixture is allowed to stand
overnight whereafter the precipitating mixture is filtered and
washed with water in order to remove acid. 4.84 g. (97%) of the
named compound are obtained. M.p.: 166.degree.-168.degree. C. After
recrystallization from methanol the product melts at
170.degree.-171.degree. C.
Minimal inhibitory concentration inhibiting the growth of
Trichophyton mentagrophytes: 2.5 .mu.g./ml., of Epidermophyton
floccosum: 5.0 g./ml.
EXAMPLE 7
1-(3-Acetoxy-4-methoxycarbonyl-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,
5-dione
4.05 g. (0.01 mole) of
1-(3-acetoxy-4-methoxycarbonyl-phenyl)-3-cyclohexylthio-pyrrolidine-2,5-di
one are suspended in a mixture of 10 ml. of glacial acetic acid and
10 ml. of acetic acid anhydride. A 30% solution of 4.8 ml. (0.05
mol) hydrogen peroxide is added dropwise. The reaction mixture is
stirred at room temperature until it is completely dissolved and
the mixture is then stirred for further 5 hours under cooling with
ice and water. The pure solution is allowed to stand overnight,
poured on ice, the precipitated product is filtered and acid is
removed by washing with water. 3.8 g. (87%) of the named compound
is obtained. M.p.: 174.degree.-176.degree. C. After
recrystallization from methanol the product melts at
177.degree.-178.degree. C.
Minimal inhibitory concentration: inhibiting the growth of
Trichophyton metagrophytes: 2.5 .mu.g./ml. and of Epidermophyton
floccosum is 10 .mu.g./ml.
EXAMPLE 8
1-(3-Acetoxy-4-carboxy-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione
8.24 g. (0.03 mole) of
1-(3-acetoxy-4-carboxyphenyl)-pyrroline-2,5-dione are dissolved in
80 ml. of dioxane and 3.6 ml. (0.03 mole) of cyclohexane-thiol are
added. Two drops of triethylamine catalyst are then added dropwise
to the reaction mixture and the mixture is kept at
80.degree.-90.degree. C. for 4 hours. The solvent is distilled off
in vacuo. As a residue an oily
1-(3-acetoxy-4-carboxy-phenyl)-3-cyclohexylthio-pyrrolidine-2,5-dione
is obtained. The product is dissolved in a mixture of 30 ml. of
glacial acetic acid and 30 ml. of acetic anhydride and under
cooling with icy water and stirring 14.4 ml. (0.15 mole) of a 30%
hydrogen peroxide solution are added dropwise. The cooling is
ceased and the reaction mixture is allowed to warm up to 30.degree.
C. The mixture is the cooled again with icy water to 0.degree. to
5.degree. C. and stirred at this temperature for 5 hours. The
reaction mixture is allowed to stand overnight. The next day the
pure solution is poured on ice and the precipitated product is
filtered and washed with water to remove acid. M.p.:
155.degree.-158.degree. C. Yield: 6.7 g. (52.9%). After
recrystallization from 50% ethanol the product melts at
160.degree.-161.degree. C.
According to the method disclosed in the Examples the following
compounds of the formula I are prepared:
1-ethyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione, yield: 47.6%,
m.p.: 118.degree.-120.degree. C.,
1-n-hexyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione, yield:
39.8%, m.p.: 127.degree.-130.degree. C.,
1-(2-chlorophenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione,
yield: 71.4%, m.p.: 153.degree.-155.degree. C.,
1-(3-nitrophenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione,
yield: 92%, m.p.: 145.degree.-148.degree. C.
1-(4-acetylphenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione,
yield: 79.1%, m.p.: 203.degree.-206.degree. C.,
1-(4-Methoxyphenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione,
yield: 85.7%, m.p.: 139.degree.-140.degree. C.,
1-benzyl-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione, yield: 84%,
m.p. 160.degree.-62.degree. C.,
1-phenyl-3-cyclopentyl-sulfonyl-pyrrolidine-2,5-dione, yield:
60.2%, m.P. 158.degree.-159.degree. C. (crystallized from
ethanol),
1-(p-tolyl)-3-cyclopentyl-sulfonyl-pyrrolidine-2,5-dione, yield:
86.1%, m.p.: 178.degree.-180.degree. C. (crystallized from
ethanol).
1-(p-sulfophenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione,
yield: 56.2%, m.p.: 230.degree.-236.degree. C.,
1-(4-methyl-2-sulfophenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione,
yield: 53.1%, m.p.: 244.degree.-247.degree. C.,
1-(3,4-dihydroxy-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione,
yield: 91.8%, m.p.: 186.degree.-188.degree. C.,
1-(4-methyl-3-carboxyphenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione,
yield: 46.7%, m.p.: 184.degree.-188.degree. C.,
1-(4-methyl-2-hydroxymethyl-phenyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-d
ione, yield: 86.2%, m.p.: 174.degree.-177.degree. C., and
1-phenyl-3-cyclocctyl-sulfonyl-pyrrolidine-2,5-dione.
The following Examples show the formulation of the active
ingredients of the formula I into fungicidal compositions without
limiting the scope of invention to the Examples.
Example a
Ointment
A homogeneous mixture is prepared in a stirring machine from the
following components:
______________________________________ active ingredient of the
formula I 2.0 g. propyl-(p-hydroxy-benzoate) 0.06 g.
methyl-(p-hydroxy-benzoate) 0.14 g. crystalline magnesium sulphate
0.30 g. white wax (Cera alba) 1.00 g. glyc glycerol 5.00 g. Miglyol
812* 8.00 g. liquid paraffin 8.00 g. Dehymuls F* 8.00 g. Cetiol V*
10.00 g. white vaseline 10.00 g. distilled water up to 100.00 g.
______________________________________
The obtained ointment is filled into tubes or jars.
Substances labelled with * have the following chemical
components:
Miglyol 812 a mixture of esters of C.sub.8-12 fatty acids with
glycerol. It is an additive promoting the homogenization of the
components. Manufacturer: Chemische Werke Witten GmbH, Witten, West
Germany.
Catiol V: deciloleate: Manufacturer: Dehydag, Dusseldorf, West
Germany.
Dehymuls F: an aliphatic ester mixture, emulgeator. Manufacturer:
Dehydag, Dusseldorf, West Germany.
Example b
Talc
A homogeneous powder mixture is prepared from the fine powder of
the following components:
______________________________________ active ingredient of the
formula I 2.00 g. colloidal silicon dioxide 1.00 g. magnesium
stearate 1.00 g. zinc oxide 2.00 g. white clay 5.00 g. magnesium
carbonate 10.00 g. talc 79.00 g.
______________________________________
The powder mixture is filled into boxes.
Example c
Aerosol composition
A mixture is obtained from the following components:
______________________________________ active ingredient of the
general formula I 0.80 g. abs. alcohol 11.00 g. Miglyol B12 12.00
g. methylene chloride 17.60 g.
______________________________________
and the mixture is filled into aerosol bottles. The bottle is
supplied with a feeder valve and finally it is filled up with an
aerosol propellant, such as a mixture of halogenated
hydrocarbons.
The compositions (a)-(c) were subjected to the same microorganism
inhibitory test as described in connection with the active
ingredients. Results of the test carried out with
1-(p-tolyl)-3-cyclohexyl-sulfonyl-pyrrolidine-2,5-dione are given
below.
______________________________________ ointment aerosol talc
minimal inhibitory concentrations in Test- .mu.g./ml. micro-
24/48/72/144 24/48/72/144 organism hours 24/48/72/144 hours hours
______________________________________ "1" 25/25/--/-- 2.5/5/--/--
25/50/--/-- "2" 25/75/--/-- 25/75/--/-- 50/75/--/-- "3" 25/50/--/--
25/50/--/-- 50/75/--/-- "4" --/--/50/75 --/--/25/50 --/--/50/50 "5"
--/--/50/100 --/--/50/50 --/--/75/100 "7" --/--/10/10 --/--/2,5/10
--/--/10/10 "9" --/--/10/75 --/--/25/50 --/--/25/50 "12"
--/--/25/75 --/--/10/25 --/--/10/10 "13" --/--/10/50 --/--/1/5
--/--/5/10 "14" --/--/10/25 --/--/1/2,5 --/--/10/25 "21"
10/25/--/-- 2.5/10/--/-- 25/25/--/-- "22" 25/50/--/-- 10/25/--/--
25/25/--/-- "15" --/--/5/10 --/--/2.5/2.5 --/--/10/10 "11"
--/--/10/25 -- /--/10/10 --/--/10/25 "18" --/--/100/100 --/--/50/50
--/--/75/100 "17" --/--/75/75 --/--/25/25 --/--/75/100
______________________________________
* * * * *